Transdermal drug delivery systems have, in recent years, become an increasingly important means of administering drugs. Such systems offer advantages which are clearly not achievable by other modes of administration such as avoidance of the gastro-intestinal tract and "first-pass" through the liver, application close to the site of action, sustained action which can readily be adjusted, etc. Clearly then, such systems will become of even greater significance in the future.
Typical transdermal systems currently known are disclosed in U.S. Pat. Nos. 3,598,122; 3,598,123; 3,742,951; 3,797,494; 3,948,254; 3,996,934; 4,284,444; and 4,597,961. These systems fall essentially into two catagories, the "matrix" resevoir type and the "membrane bag" reservoir type. Each type has some kind of backing material, a drug reservoir, and an adhesive. The backing material is inert to the drug (or drug formulation) and adhesive and does not permit any of the drug formulation to migrate through it.
In matrix type systems, the drug resevoir is a matrix in which the drug is dispersed and through which it may migrate by diffusion or microporous flow. The matrix material may simultaneously act as an adhesive as well; in which case only an occlusive, removeable covering is required to complete the system. When the matrix material is not an adhesive, a suitable adhesive is also necessary to mount the matrix on the backing material as well as to the removeable occlusive covering. Alternatives to adhesives to secure the "matrix" to the backing material and removeable occlusive covering include compression fitting and "hot melting" including thermal impulse and ultrasonic welding.
In "membrane bag" type systems, a drug permeable membrane is mounted on the backing layer to define a pouch (either by adhesive, compression fitting or hot melting) or two membranes are sealed together to define a "bag" which is mounted on the backing with a suitable adhesive. Adhesive is also required on the bag's surface distal to the backing layer to affix an occlusive removeable covering.
In each of these systems the drug contained in the system is, at all relevant times, capable of crossing all of the system components which would be interposed between the drug and the removeable, occlusive covering, or patients skin.
While these known systems are quite useful, they also have severe drawbacks and limitations to their use. One of the most important drawbacks of the known transdermal systems is intimately related to the properties which make the route of administration possible at all, the ability to permeate intact skin. Because the active agent can (or the formulation containing it permits it to) permeate intact skin and quite potent agents are being used, extreme caution must be used in the manufacturing process. Here, bulk quantities of potent agents are being utilized and even minor "accidents" can result in severe medical emergencies. Small amounts which contaminate clothes can find their way onto worker's skin and then into their bodies. As such workers deal with the drug on a frequent basis, unless the utmost care is taken, these people can receive many times the therapeutic dose of the active agent. This problem is of even greater concern when the active agent has a high vapor pressure resulting in vapor settling on clothes, uncovered skin or elsewhere.
Another problem of the known transdermal systems is that frequently the permeating form of the drug is not suitably stable; therefore, the shelf life of the system would be too short to be commercially practical. A third problem encountered by the known transdermal systems is the problem of "drug leakage", primarily through the adhesive. The drug must be able to migrate through or around the adhesive. Since it can, it will redistribute itself from the reservoir into the adhesive, and if the adhesive (and permeable membrane) have edges which are not surrounded by an occlusive covering, drug loss results.
In addition, transdermal systems of the art are limited to regulating drug delivery by only a few, very limited means; drug concentration, membrane or matrix material and thickness, and flux enhancers. However, once the parameters are chosen, only a single release rate results per system. The only exception to this is in the case where the adhesive between the reservoir and the removeable, occlusive covering absorbs a portion of the drug. In this case, an initial "burst" effect is observed. The amount of drug initially delivered is higher and then tapers off to a sustained release level.
Another problem encountered with known transdermal devices is how to know when it is time to change the device for a fresh one. Dosing of any medication, by almost any route of administration has largely been one of "approximately" and "trial and error". This is especially so with respect to ambulatory patients and long term medication.
Therefore, one of the objects of the invention is to provide a transdermal system which overcomes these and other defects.
It is an object of the invention to provide a transdermal system which can be manufactured with greater safety with a broader range of active agents than previously possible.
It is another object of this invention to provide a transdermal system which is less hazardous to the user during its application to the patients skin.
It is an additional object of the invention to provide a transdermal system which has greater storage stability than the known systems.
Another object of the invention is to provide a transdermal system whose release characteristics can be designed in a manner to allow a complex arrangement of drug delivery regimens in a single system.
A still further object of the invention is to provide a change in the device perceptible to the user to indicate the system no longer contains an adequate drug supply.
A still further object is to deliver topical drugs to a patient's skin in accordance with the foregoing objects.